Introduction
The prevalence of dementia is expected to triple by 2050 [
1]. In the past few decades, there has been an “Alzheimerization” of dementia with a tendency to attribute all cognitive decline to Alzheimer’s disease (AD) [
2]. This view is now being revised with the recognition of the major vascular contribution to dementia [
1,
3‐
5]. Vascular cognitive impairment (VCI) is the term that encompasses the clinical spectrum from mild cognitive dysfunction to vascular dementia. The NINDS Stroke Progress Review Group in 2012 cited “prevention of VCI” as a major research priority (
http://www.ninds.nih.gov/find_people/ninds/OSPP/Stroke-Research-Priorities-Meeting-2012.htm).
The pathological hallmark of VCI is white matter (WM) damage from ischemia in the periventricular regions and centrum semiovale [
1,
5]. The imaging correlate of this WM damage is “leukoaraiosis” [
6]. The degree and severity of leukoaraiosis are associated with cognitive impairment, depression, gait abnormalities, and disability [
6]. There is no known treatment once symptoms appear although observational studies suggest exercise (probably due to upregulation of endogenous protection) may slow down cognitive decline [
7]. WM changes are mediated by vascular dysfunction and inflammation, blood-brain barrier (BBB) leakage, glial activation and injury to oligodendrocytes, and finally demyelination [
1]. Reduction in the cerebral blood flow (CBF) leading to hypoperfusion is an early and characteristic finding [
1].
Remote limb ischemic conditioning (RLIC) is the simple, inexpensive, and safe use of repetitive inflation-deflation procedure of a blood pressure (BP) cuff on the arm or leg to protect distant organs such as the brain, heart, and kidney from ischemic injury [
8]. A number of preclinical studies also demonstrated that RLIC is effective at reducing injury in focal cerebral ischemia models (recently reviewed by us) [
8]. We demonstrated that RLIC is protective and increases CBF in a murine model of thromboembolic stroke [
9,
10]. Moreover, in patients with intracranial arterial stenosis, RLIC increased CBF as measured by SPECT [
11]. Therefore, the mechanism of this protection may partially rely on the improvement of CBF.
There are a number of proposed animal models for VCI. In a recent review of all mouse models for VCI and vascular dementia [
12], Bink and colleagues found that the mouse bilateral common carotid artery stenosis (BCAS) model to be the best and most valid [
13]. This model reproduces cerebral hypoperfusion, inflammation, BBB damage, WM damage, and cognitive deficits of the human condition [
13,
14]. It also avoids damage to the visual pathways, a complication of rat model of carotid ligation. We hypothesized that remote ischemic postconditioning (RIPostC) will improve CBF and behavioral outcomes and reduce inflammation and WM damage in this murine BCAS model of VCI.
Discussion
This is the first report in any animal model of VCI where RLIC has been tested. Our major findings are that RIPostC in the murine BCAS model improves CBF and cognitive function and reduces inflammation and neurodegeneration. Long-term (2 weeks) RIPostC therapy significantly increased the CBF in a sustained fashion and improved cognitive function. CBF remain increased for at least 1 week even after the cessation of long-term RIPostC therapy (Fig.
1). We also found reduced Aβ level in RIPostC-treated group that might be attenuated due to the improved CBF and subsequent clearance of Aβ [
19]. BCAS in mice triggers a proinflammatory milieu and impairs microvascular dysfunction, as evident by the increased gene expression of ICAM-1 and VCAM-1 (Fig.
2) [
20]. ICAM-1 and VCAM-1 promote adhesion phenomena resulting into disintegration of BBB and increased infiltration of proinflammatory immune cells, which amplifies the neuro-glial inflammation, WM degeneration, and cell death (Figs.
2,
3,
4,
5,
6). When treated, RIPostC therapy not only reduced the vascular inflammatory responses but it also downregulated GFAP (astrocytes) and IBA-1 (microglial) expressions, subsequently leading to reduced WM changes and neurodegeneration.
There are no known treatments for VCI. Therapies are needed to prevent the transition and progression of the disease process to dementia. A potential target population for RLIC may be patients with “leukoaraiosis” on MRI. The Leukoaraiosis and Disability cohort (LADIS) is a European multicenter collaboration with the aim to predict disability in the patient aged 65–84 years with leukoaraiosis [
6,
22]. These patients suffer from cognitive impairment, gait instability and falls, depression, and urinary incontinence. The degree of leukoaraiosis is associated with cognitive impairment, and the progression of leukoaraiosis on MRI strongly predicts cognitive decline [
23,
24]. There is no known treatment to slow down the cognitive decline, but observational studies suggest that physical activity (which modulates endogenous protection as well as CBF similar to RLIC) might be of benefit [
7]. From the LADIS cohort, estimates of sample size for a clinical trial with an intervention to reduce progression of WM changes on MRI range from 58 to 70, highlighting the potential translational pathway for RLIC. Moreover, RLIC is feasible for long-term treatment and comparatively more conventional for aged individuals with gait problem. A small size Chinese trial reported that RLIC increases CBF in patients suffering from intracranial arterial stenosis and prevents recurrent stroke [
11]. It also demonstrates that this therapy using a BP cuff has long-term feasibility, as they were able to treat patients for 300 days.
Our study has several limitations. First, our number of animals is small (N = 20), but the study is randomized, blinded, and adequately powered. The effects observed were robust, however, indicating that large sample sizes are not needed. Second, while the BCAS model is regarded as the most valid for VCI, it does not recapitulate small vessel disease, the underlying pathophysiology of VCI. While the model produces chronic hypoperfusion, it does this via obstruction of the larger blood vessels affecting microvascular flow but the pathology is itself not intrinsic in the smaller vessels. Moreover, the disease process has a defined start whereas in humans, it is insidious with slow onset. Third, we treated and followed these mice for a relatively shorter period of time, 28 days. Fourth, we used young male mice, and VCI is a disease of the elderly. Fifth, in this translation report, we did not investigate the mechanism of protection by RIPostC. We now have ongoing work to test RIPostC therapy in aged mice of both sexes; MRI to see WM changes, and study the possible mechanism of vascular protection by long-term RIPostC therapy.
In summary, RIPostC therapy increases CBF and improves cognitive performance in a murine model of VCI. This therapy is highly translatable to humans. If successful, this no-additional cost therapy using BP cuff will be an “exercise equivalent” which will be highly convenient for elderly patients as well as caretakers to perform, and therefore, may change the current therapeutic paradigm of VCI in humans.
Acknowledgments
This work was supported by the GRU start up fund to MNH and R21NS081143 award to DCH. Partial supports from R01NS065172, R21NS075774 and R03NS084228 to KMD, VA Merit Awards BX000347 and R01NS083559 to AE, and VA Merit Awards BX000891 and R01NS063965 to SCF are also acknowledged. Adviye Ergul is a research pharmacologist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia. The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government.